This present invention relates to methods to limit scar and adhesion formation.
Wounds in mammalian tissue result in tissue disruption and coagulation of the microvasculature at the wound face. Repair of such tissue represents an orderly, controlled cellular response to injury. The cellular morphology consists of three distinct zones. The central avascular wound space is oxygen deficient, acidotic and hypercarbic, and has high lactate levels. Adjacent to the wound space is a gradient zone of local anemia (ischemia) which is populated by dividing fibroblasts. Behind the leading zone is an area of active collagen and other extracellular matrix protein synthesis characterized by mature fibroblasts and numerous newly-formed capillaries (i.e., neovascularization).
Tissue injuries, such as an injury to the skin due to a laceration, a puncture, or a burn result in a wound that can extend into or through the tissue. If the wound is fairly small and localized, normal healing processes can close the wound and restore normal function to the tissue. (Id.) In some cases, however, an injury results in a deep wound or a wound that affects a large area. Such wounds can require clinical intervention for healing to occur. Wound closure is achieved by the combined action of keratinocyte migration into the wound site and contraction of specialized fibroblasts in the tissue underneath the wound site, which pulls the edges of the wound closer together. Inefficient remodeling of the wound bed leaves a scar, and in severe cases can lead to loss of tissue function at the wound site.
Scars can be defined as a macroscopic alteration in the appearance of the skin resulting from some type of wound, often due to an abnormal organization of dermal connective tissues and their associated cells. (Chamberlin et al., J. Anat. 186:87-96 (1995)) A scar is an imperfect substitute for the original tissue, since it serves as a diffusion barrier to nutrients and oxygen, has a lower breaking strength, and often results in deformation, reduction in function, and impairment of growth of the original tissue. The only advantage offered by a scar is the rapidity by which it allows structural integrity to be established. Thus, the ideal situation for a healing wound would be a rapid closure of the wound and regeneration of the dermal architecture without the formation of a scar and its resultant deleterious effects on growth, function, and appearance. (Chamberlin et al., J. Anat. 186:87-96 (1995))
Fetal wounds, unlike those in the adult, heal without scar formation and with a reduced growth factor profile and inflammatory response. (Chamberlin et al., J. Anat. 186:87-96 (1995)) It has also been demonstrated that, in a well characterized aging mouse colony, the rate of scarring is reduced with age, while healing is delayed in terms of re-epithelialization and basement membrane and matrix deposition. (Ashcroft et al., J. Anat. 190:351-365 (1997)). Thus, the processes of wound healing and scar formation are separable.
Previous studies have demonstrated that a reduction in the levels of transforming growth factor xcex2-1 and xcex2-2 (TGF xcex2-1 and TGF xcex2-2) in healing adult rodent dermal wounds produces no deleterious effects on the speed or strength of wound healing, but provides a reduction in scarring. (Chamberlin et al., J. Anat. 186:87-96 (1995)) Wounds treated with a neutralizing antibody to TGF-xcex21 have a lower inflammatory response, reduced early extracellular matrix (ECM) deposition, and reduced later cutaneous scarring. (Shah et al., Am. J. Pathol. 154:1115-1124 (1999) In contrast, increasing the local tissue levels of TGF-xcex21 increases early ECM deposition, but does not alter scar formation. Thus, factors that promote wound healing do not necessarily limit scar formation.
Scarring is a major cause of many clinical problems. Post-burn contractures, post-operative adhesion and strictures causing intestinal obstructions, mid-facial contractures following cleft palate surgery, and painful neuromas are but a few examples of the problems caused by scarring. Scar tissue interferes with growth, caused deformities, impairs function, and is aesthetically unsightly. (Shah et al., J. Cell Science 107:1137-1157 (1994)).
Similarly, post-operative adhesion formation is a major source of postoperative morbidity and mortality after many surgical procedures, including abdominal, pelvic, thoracic, and other surgical procedures. The pathogenesis of adhesion formation is complex and not entirely understood. The first step is believed to involve excess fibrin deposition to form a scaffold. Organization of the fibrin scaffold by cellular elements, including fibroblasts and mesothelial cells, then follows. A variety of approaches for the prevention of adhesion formation have been actively explored. (See, for example, U.S. Pat. Nos. 5,891,460; 5,639,468; 5,629,294; 5,614,515; 5,534,261; 5,498,613 and 5,478,837; all herein incorporated by reference in their entirety.) However, no single therapeutic approach has proven universally effective in preventing adhesion formation after surgery, or other types of wounds.
Therefore, there is a need for compositions and methods which may be used safely and effectively to limit scar and adhesion formation.
The present invention provides pharmaceutical compositions, methods, and kits for limiting scar and adhesion formation, comprising administering to a mammal in need thereof an amount effective to limit scar or adhesion formation of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII) analogues, AII fragments or analogues thereof, ACE inhibitors, or AII AT2 type 2 receptor agonists, either alone or in combination with other compounds.